Steinman J L, Carlton S M, Haber B, Willis W D
Geriatric Research, Education and Clinical Center, VA Medical Center, Sepulveda, CA 91343.
Brain Res. 1987 Nov 24;426(2):297-309. doi: 10.1016/0006-8993(87)90883-3.
The involvement of endogenous serotonergic pathways in the mediation of antinociception has been indicated by electrophysiological, pharmacological and behavioral experiments. However, manipulation of the indole pathway, either by lesioning of raphe nuclei or drug intervention, often produces disparate results. In particular, serotonin (5-HT) synthesis inhibition with p-chlorophenylalanine (PCPA) has been reported to produce either hyperalgesia or analgesia, depending upon the type of pain measurement examined. In the present study, we sought to evaluate the effects of PCPA on (1) behavioral responses to noxious stimulation, and (2) levels of serotonin, tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) in raphe nuclei (pallidus, obscurus, magnus and dorsalis) and spinal cord regions by HPLC with electrochemical detection. Treatment of rats with 400 or 600 mg/kg of PCPA for 3 consecutive days resulted in significant elevations in pain thresholds assessed by tail withdrawal from radiant heat as well as vocalization to electric shock of the tail. The effect of PCPA on vocalization threshold was particularly striking, for the majority of animals showed a nociceptive-specific attenuation of this response. Although the PCPA induced changes in indole content of the various raphe nuclei were not unequivocally dose-dependent, differential reductions of serotonin and 5-HIAA were clearly detected in the various raphe regions. Nuclei raphe pallidus and obscurus were depleted of 5-HT and 5-HIAA to the greatest extent, whereas levels detected in nuclei raphe magnus and dorsalis were reduced by 30-40% from control values. Metabolism of 5-HT and 5-HIAA appeared unaffected by PCPA in all regions examined except the dorsal portion of the spinal cord. These findings collectively suggest that the effects of PCPA are not uniform throughout the central nervous system and raise the possibility that discrepancies in the behavior literature may be attributed to drug-induced changes in some, but not all serotonergic pathways.
电生理、药理学和行为学实验表明，内源性血清素能通路参与了痛觉缺失的调节。然而，通过损毁中缝核或药物干预来操纵吲哚通路，往往会产生不同的结果。特别是，据报道，用对氯苯丙氨酸（PCPA）抑制血清素（5-HT）合成会产生痛觉过敏或镇痛作用，这取决于所检测的疼痛测量类型。在本研究中，我们试图评估PCPA对（1）对伤害性刺激的行为反应，以及（2）通过高效液相色谱电化学检测法测定中缝核（苍白核、 obscurus、大核和背侧核）和脊髓区域中血清素、色氨酸和5-羟吲哚乙酸（5-HIAA）水平的影响。连续3天用400或600mg/kg的PCPA处理大鼠，导致通过辐射热尾部撤离以及尾部电击发声评估的疼痛阈值显著升高。PCPA对发声阈值的影响尤为显著，因为大多数动物表现出这种反应的伤害性特异性减弱。尽管PCPA诱导的各种中缝核吲哚含量变化并非明确的剂量依赖性，但在各个中缝区域明显检测到血清素和5-HIAA的差异减少。中缝苍白核和obscurus核的5-HT和5-HIAA耗竭程度最大，而中缝大核和背侧核中检测到的水平比对照值降低了30-40%。除脊髓背侧部分外，在所检查的所有区域中血清素和5-HIAA的代谢似乎不受PCPA影响。这些发现共同表明，PCPA在整个中枢神经系统中的作用并不一致，并增加了行为学文献中的差异可能归因于药物诱导的某些而非所有血清素能通路变化的可能性。
